Poliomyelitis has afflicted humankind since antiquity, and for nearly a century now, we have known the causative agent, poliovirus. This pathogen is an enterovirus that in recent history has been the source of a great deal of human suffering. Although comparatively small, its genome is packed with sufficient information to make it a formidable pathogen. In the last 20 years the Global Polio Eradication Initiative has proven successful in greatly diminishing the number of cases worldwide but has encountered obstacles in its path which have made halting the transmission of wild polioviruses a practical impossibility. As we begin to realize that a change in strategy may be crucial in achieving success in this venture, it is imperative that we critically evaluate what is known about the molecular biology of this pathogen and the intricacies of its interaction with its host so that in future attempts we may better equipped to more effectively combat this important human pathogen.